Process fob preparation of vitamin



Patented Aug. 19, 1941 PROCESS FOR PREPARATION OF vrrsmn B1 Zoltan Fiildi and Amid Gerecs, Budapest, Hungary N Drawing. Applicatio No. 373,518. In Hu 6 Claims.

Several methods are already known for preparing vitamin 131. One of them is starting from ready made thiazoles' and is bringing these into reaction with suitably substituted pyrimidine derivatives, such pyrimidine derivatives carrying a halogeno-methyl, or a hydroxy-methyl, or alkoxy-methyl group in position 5. (See e. g. the British specification 496,726, the German specification 669,187, the German specification 685,- 032 and the U. S. A. specification 2,209,244.) In another known process (see e. g. specification No. 471,416) suitably substituted -thioformamidomethyl pyrimidines are condensed with an ester of a -aceto-v-halogeno-propyl alcohol. Still another process consists in condensing an store 11 January 7, 1941, Serial 88-11 January 25,1940

mentioned thioformamidomethyl pyrimidine with 2 methyl 2 alkoxy-3-halogeno-tetrahydrofurane. (See e. g; U. S. A. specification No. 2,127,446.)

The process referred to above became known partly by the scientific and partly by the patent literature. From the scientific literature it seems established, that the -acetow-halogeno-propylalcohols do not form vitamin B1 on treatment with the substituted 5-thioformamidomethylpyrimidines. Thus, for instance, Todd and Bergel mention in a research paper of theirs (published in the Journal of the Chemical Society, 1937, pp. 364-367) inter alia: Compounds (I) (i. e. 2methyl-4-amlno-5-thioformamidomethyl-pyrimidine) and (II; R=H) (i. e. 'yaceto-v-chloro-propyl' alcohol) did not yield aneurin when heated together in dioxan solution, but whens. mixture of the two compounds alone was heated at 140 reaction occurred with considerable darkening and resinification. From the product a substance was isolated in poor yield which had the properties or aneurirz. The low reactivity of the hydroxyketone (II; R=H (the v-aceto-' -chloropropyl alcohol) which probably exists mainly in the cyclic oxide form, has already been mentioned.

It is apparent from the above quotation, as also from other statements, that until new vitamin B; could not be prepared by the interaction of a corresponding thioformamidomethyl-pyrimi dine and -aceto-- -chloropropyl alcohol. also Todd and Bergel found in their above paper necessary to use the acetic ester of the 'y-acetm'rchloro-propyl alcohol in the condensation of 5 thioformamidomethyl-pyrimidine to vitamin 381 and even in this case the yield was inconsiderable. 7

Our experiments have led to the observation 7 that the compound which is known in the'literadioxane solution, the present process gives, ing out the same starting materials, excellent v In the following description for the -y-aceto-'ysulphonic acid,

ture as 'y-aoeto y-halogeno-propyl alcohol, which has, however, the cyclic form of 2-methyl-2-. hydroxy-3-halogenotetrahydrofurane is able to produce in excellent yields vitamin B1, it the reaction is carried out, in the presence of salts of weak organic bases formed with strong acids. The importance of such salts emerges clearly from the following comparison: while Todd and Ber-gel were unable to obtain vitamin 131 from 2- methyl-4-amino-5-thioformamidomethyl-pyrimidine and v-aceto-y-chloro-propyl alcohol in carryreaction in the presence of pyridine hydrochloride and halogeno-propylalcohol the name of 2.-methyl- 2-oxy-3-halogenotetrahydrofurane, i. e. the-name of the cyclic form is used and similarly for the 'y-aceto-y-chloro-propyl alcohol the name of 2- methyl 2 on-Z-chloro-tetmhydrofurane. This latter substance can be obtained from c-ChlOlO-daceto-butyrolacton in the way which is given in the literature (see Journ. Amer. Chem. Soc, vol.

58, p. 1804) for the ohtention of 7-868t0-7-0h1010- propyl alcohol with the remark, however, that the raw w-aceto-q-chlorc-propyl alcohol is preferably to be subjected in a high vacuo to a careiul fractional distillation and that fraction is preferably to be used which boils at 106-103" under a pressure of about 7 mm. Hg. This fraction shows on the test of Eerewiifinofi tor active hyinconsideratile amounts of active drogen only very hydrogen.

The salts, that are according: our invention necessary ferthe reaction, are preferably salts of weak tertiary bases pyridine," quinoline, dimethyls as acid components of these .haloid-acids or other strong;

Salts Preemie/in mineral acid gl'ggmg; gems? as e benzene ruin B1 is nsesl or" its hydrochloride, one may use preiera hydrochlorides of weak bases.

The is led out preierahly at peratures ticim. iii; higher tempera tures side-reone are likely to take place. lower cs, however. the duration oi? reaction to be prcioneierl. it found pra' cal to carry out the condensation in lit-25 hours at about 7ft or in 3M1 hours at 513-. 01' course, considerable quantities or? 331 are formed. even in much shorter time.

The salts er weak leases with strong acids, like pyridine-hydrochloride, or dimethylaniiine-hydrochloride, are suitably employed in such errant-i using theyery same yields of vitamin B1. 7

a be taken. however,

that they can take over also the part of a g. to 1 part of 2-methyl-4- ties, solvent or diluent: e.

amino- 5 -thioiormamido-methyl-pyrimidine 2-6' pyridine-hydrochloride and about 0.4 part of water and with about 1-1.4 part of aceto-chloropropyl alcohol (2-methyl-2-hydroxy-3-chlorothese solthe vitamin is obtained as a colorless crystalpowder.

which disappear on shaking for a short time ina I tetrahydrofurane) The mass is mixed over until it becomes practically homogeneous, after which-the solution is subjected to further heating to 70 for 15-20 hours, or to 50 for 45 hours. Into the above mixture also about 0.8 parts (related to the amount of the thioformamldomethylpyrimidine compound) of absolute alcohol and/or 0.05-0.12 part of pyridine may be added. Instead of pyridine-hydrochloride also dimethylaniline-hydrochloride can be employed.

In course of the heating vitamin B1 separates I in form of a crystal mass. At lower temperatures the coloration of the mixture is of lesser degree than at higher temperatures.

The reaction mixture is worked-up in a simple way. Small amounts of absolute alcohol are added to, mixed over and, if necessary, heated for a short while, then absolute alcohol containing hydrogen chloride is added and after some standing the separated hydrochloride of the vitamin is pressed up on a Biichner funnel. If the reaction was carried out at low temperature, the vitaminhydrochloride is a nearly colorless crystal powder.

Samples of vitamin obtained from reaction conducted athigher temperatures are contaminated by minute amounts of tarry material. This contamination can be removed,- however, by dissolving the hydrochloride in a littlewater and illtrating. Purification through the picrate or the picrolonate is in this process wholly superfluous. The yields are excellent; from 1 part of' thioformamido-methyl-pyrlmidine 1-1.3 parts by weight of vitamin can be obtained.

Further details of the process can be seen from the following examples:

.(1)- 1 ccm. of dry pyridine is mixed with 2 com. of abs. alcohol which contains of hydrogen chloride and then the alcohol is removed by distillation and the residue is heated in vacuum until the weight becomes constant. The residue (about 1.55 g. of pyridine-hydrochloride) is mixed then with 0.5 g. of 2-methyl-4-amino-5- thioformamidomethyl-pyrimidine and 0.6 ccm. of alcohol (aceto-chloro-propyl alcohol). The mixture is now brought to melting by heating to 80 while thoroughly mixing, and this faintly colored solution is kept at 70 for 18 hours in an incubator. After 3 hours the separation of the vitamin begins already in form of a crystal mass. After the 18 hoursof incubatiomthe mixture is mixed with 3 com. of abs. alcohol and 0.3-0.5 ccm. of alcohol containing 25% of hydrogen chloride heated for a short while on a steam-bath and chilled afterwards in ice-water. The crystal mass is then filtered on a glass filter and washed with absolute alcohol. 0.62 g. of a slightly grey crystal powder of the m. p. 245 is obtained. If the product is dissolved inwater, filtered, the

tal mass is mixed with abs. alcohol and auctioned,

of water are added to the reaction mixture. One

observes on the beginningof the heating 2 layers same manner as described in the foregoing example. One obtains 0.67 g. of vitamin having a melting point of about 239-240? C. It can be separated from the slightly coloring lay-products by recrystallizing from aqueous alcohol or by the method of the foregoing example.

(3) 0.5 g. of 2-methyl-4-amino-5-thioformamidomethylpyrimidine, '.3' g. of distilled pyridine-hydrochloride and 0.6 ccm. of 2-methyl-2- at about 80 to a homogeneous solution which is then kept on about 70 for 15-20 hours in an incubator. The working-up of the mixture is carried out by the methods' of. the foregoing'exampies. One obtains 0.52-0.55 g. of vitamin, having a melting point of about 242 C. Further quantitles of vitamin can be obtained from the mother liquors.

' (4) 1 g. of anhydrous pyridine is mixed with 2 com. of abs. alcoholcontaining a quantity of hydrogenchloride equivalentto the pyridine. 0.5 g. 2-methyl-4-amino -5- thioformamido-methyl-pyrimidine and 0.6 g; of 2-methyl-2-hydroxy-3- lized out in rich quantity few ccm. of abs. alcohol and little abs. alcohol containing hydrochloride gas are added. After standing and cooling the crystals are filtered by suction. About 0.43- 0.47 g. of crystals of vitamin are obtained. The product melts at about 239240- C. and can be, if wanted, purified by the methods described in the foregoing examples. Further quantities of vitamin can be isolated from the mother liquors.

(5) 1.5 g. distilled pyridine hydrochloride, 0.5 g. 2-methyl-4-amino-5-thioformamidomethylpyrimidine and 0.6- g. of .2-methyl-2-hydroxy-3- chloro-tetrahydroiurane are melted and homo- .genized at 70. The obtained pale yellow reaction mixture is kept for hours in an incubator at The reaction mixture crystallizes; its working-up is carried out as described in the foregoing examples. One obtains about 0.5-0.55

g. ofv vitamin melting at about 240. Further quantities of vitamin can be won from the mother liquors.

(6) Starting'from 1.3 g. quinoline and irom abs. alcohol containing hydrogenchloride gas the quinoline hydrochloride is prepared and the diluent is removed in vacuo. 0.5 g. 2-methyl-4-amino- 5-thioformamidomethyl-pyrimidine and 0.6 g. of

water removed in vacuum. and the residual crys- 2 methyl-2-hydroxy-3-chloro-tetrahydrofurane are added to the hydrochloride. The reaction mixture homogenized by heating is kept for 16 hours at The working-up of the mixture is carried out in analogous manner with the methods described in the foregoing examples. One obtains 0.4 g. of vitamin melting at about 239 C. Further quantities of vitamin can be recovered by evaporation of the alcoholic mother liquors hydroxy-3-chloro-tetrahydrofurane are melted heated, while stirring, to 50.

and by dissolving the residue in water and ether and by evaporating the filtered aqueous solution and by crystallizing the residue from alcohol.

(7) 1.5 g. distilled pyridine-hydrochloride, 0.5 ccm. of alcohol, 0.5 g. of 2-methyl-4-amino-5- thioformamidome'thyl-pyrimidine, 0.6 g. of 2- methyl 2 hydroxy 3 chloro-tetrahydrofurane and 2 drops (about 0.04 g.) of dry pyridine are The components of the reaction are slowly dissolved; subsequently the solution is kept for 45 hours in an incubator of 50. already after Working-up of out in the same manner as described in the abovestanding examples. The first crystal generation furnishes 0.41-0.45 g. of vitamin. Out of the mother liquors further quantities or vitamin can be obtained.

(8) Starting from 1.2 g. dimethyl-anilin and alcoholic hydrochloric acid dimethyl-anilin' hydrochloride is prepared. diluent 1.8 g. of an oily residue is obtained; (a small test portion of it blues wet conga-paper). To this oil 0.5 g. 2-methyl-4-amino-5-thioformamido-methyl-pyrimidine, 0.6 com. of 2- methyl 2 hydroxy 3-chloro-tetrahydrofurane are added; by heating gently a homogenized solution is prepared which is kept then for20 hours in an incubator of 70. The reaction mixture, thus obtained, is a deep violet red and partly crystallized mass. One obtains on working up 20 hours in rich quantity. The

- by the methods described in the foregoing examples 0.62-0.70 g. of melting at 243 C.

(9) The reaction mixture corresponds to the Example 2, but one uses 1 com. dioxan instead of 0.2 ccm. water. The reaction mixture consists, also during the heating, of two layers. The duration of the heating is about 20 hours at 70. One obtains after the methods of the foregoing examples about 0.55 g. of vitamin, which melts at 245 C.

(10) The reaction mixture corresponds to the preceding example, but one uses 15 ccm. chloroform instead of dioxan. On heating the mixture becomes homogeneous. The duration of heating as well as the temperature of the reaction corresponds to that of the preceding example. The vitamin obtained weighs 0.53-0.58 g. Melting point 240-242 9. g

(11) One prepares out of one part of dry pyridine and of abs. ethylalcohol containing hydrochloric acid gas the chlorhydrate, which is carefully freed from diluent in vacuo. 0.5 parts small shiny crystals of vitamin 2,-methyl 4-amino-5-thioformamidomethyl py rimidine and 0.6 part of chloro-tetrahydrofurane ture is heated under stirring for an hour gradually to 80 and is kept for another 3-4 hours at this temperature. Towards the end. of the 2-methyl-2-hydroxy-3- The vitamin begins to crystallize the reaction mixture is carried On elimination of the are added. The mixc-chloroa-aceto-butyrolactone by methods ef-.

heating the vitamin crystallizes out. One adds 3-5 ccm. of abs. alcohol and a little alcohol containing hydrochloric acid gas. After standing and cooling the crystals of vitamin are collected by suction. One obtains the vitamin in form of snow-white crystals M. P. at about 242-25.

It is a great advantage of the process, that according to this invention excellent yields are obtained also when carrying out the present process in industrial scale. The yields are even then excellent, when the starting materials are used in thousand-fold or more of the quantities given in I the examples.

In the interval between the convention date and the filing date of this specification a paper has been published by Stevens and Setin in the Journal of the American Chemical Society, vol. 62, pp. 1040-1049, in which paper the authors have shown that the so-called aceto-chlor-propyl alcohol, which has been supposed to exist mainly in the cyclic oxyd form, is in the reality an ether derivative of the 2-2-oxy-methyl-3-chloro-tetrahydrofurane, namely the -aceto-y-chloro-propyl ether derivative. According to this statement the real chemical structure of the compound which has been designated in the preceding examples as Z-methyl-2-hydroxy-3-chloro tetrahydrofurane, is such a one inwhich the hydroxy group in position 2 is not all free, but etherified with '7- aceto-'y-chloro-propy1 alcohol. This new statement relates, however, merely to a question of nomenclature, altering not at all either the method for the obtainment of this starting material or the reaction conditions given in the preceding examples. Of course, it is also possible to utilise in the present process-as starting material-su'ch a 2 methyl-2-hydroxy-3-chloro-tetrahydrofurane 'y-aceto-y-chloro-propyl ether, which has been prepared exactly according to Stevens and Stein.

What we claim is: v

1. A process for preparing vitamin B1, which comprises the subjecting of 2-methyl-4-amino-5- thioformamidomethyl-pyrimidine, in the presence of salts of weak strong acids, to the action of 2-methyl-2-hydroxy-3-halogeno-tetrahydrofurane.

2. A process for preparing vitamin B1, which consists in subjecting 2-methyl-4-amino-5-thioformamidomethyl-pyrimidine, in the presence of salts of weak organic bases formed with strong acids, to the action of such a fraction of 2- methyl 2 hydroxy 3 chloro-tetrahydrofurane, which fraction shows on test of Zerewitinofi for active hydrogen only very inconsiderable amount of active hydrogen.

3. A process for preparing vitamin B1, which consists in subjecting 2-methyl-4-amino-5-thioformamidomethyl-pyrimidine, in the presence of salts of weak organic bases formed with strong acids, to the action of such a fraction of 2- methyl 2 hydroxy 3 ohloro-tetrahydrofurane, which fraction distils at about 1/2 mm. Hg. pressure at -103. i V

4. A process for preparing vitamin B1, which consists in subjecting 2-methyl-4-amino-5-thiofor-mamidomethyl-pyrimidine, in the presence of salts of weak organic bases formed with strong acids, to the action of products resulting from fecting a hydrolytic opening of the furane ring and a simultaneous decarboxylation.

5. 'In the preparation of vitamin B1 by interaction of 2-methyl-4-amino-5-thioformamidomethyl-pyrimidine, in the presence of salts of weak organic bases formed with strong acids, and of a 2-methyl-2 hydroxy-3-halogeno-tetra-hydrofurane the use of a member of the group consisting of pyridine hydrochloride, dimethylaniline hydrochloride.

. 6. A process as claimed in claim 5, in which a member of the group consisting of pyridine hydrochloride, dimethyl-aniline hydrochloride is used as medium for the reaction.

zoLTAN FOLDI. ARPAD' GERECS.

organic bases formed with i 

